N-arylation of isatins

ABSTRACT

A process for the N-arylation of isatins with organo bismuth reagents is disclosed.

This application is a continuation of application Ser. No. 271,799,filed Nov. 15, 1988, which is a continuation-in-part of application Ser.No. 104,715, filed Oct. 2, 1987, entitled "N-Arylatin of Isatins" bothobtained.

BACKGROUND OF THE INVENTION

The present invention relates to a process and intermediates for theproduction of N arylated isatins which are in turn used in themanufacture of N alkyl acridine sulfonamide chemiluminescent labels.

As disclosed in copending U.S. patent application Ser. No. 921,979entitled Chemiluminescent Acridinium Salts filed on Oct. 22, 1986 byMattingly et al. (the disclosure of which is incorporated herein byreference), such salts are useful in chemiluminescent immunoassays(CLIAs). In CLIAs, an antibody (or antigen) is labeled with achemiluminescent moiety, and the labeled antibody (or antigen) isintroduced to a sample containing the corresponding antigen (orantibody) to be detected or measured. Once the labeled antibody (orantigen) binds to the corresponding antigen (or antibody), the presenceor amount of antigen (or antibody) in the sample can be determined,depending upon the type of assay format utilized. There are variousassay formats: enzyme immunoassays, radioimmunoassays, fluorescentpolarization immunoassays, and the like. Chemiluminescent immunoassaysmay thus match or exceed the sensitivity of radioimmunoassays (RIA), orenzyme immunoassays (EIA). [Kircka et al., Diagnostic Medicine, 1, 45 52(1984].

Substituted acridine 9 carboxylic acid compounds have been demonstratedto be useful in CLIAs. To make such compounds, one can directlysubstitute an existing acridine compound. However, direct substitutionoften achieves low yields, forms many isomers, and often destroys otherfunctional groups on the acridine rings. Substituted acridine 9carboxylic acid compounds can also be prepared with the Jourdan UllmannGoldberq synthesis and/or Chapman rearrangements. These procedures arelabor intensive, unfortunately, and the substituted acridines formedfrom the cyclization of diphenyl amines often cannot be converted to the9-carboxylic acids with known techniques. Finally, acridine 9 carboxylicacids can be prepared with a Pfitzinger rearrangement of isatins andketones, with subsequent aromatization of the final ring on theacridine. But, low yields are often encountered, isomers are formed, andother functionalities on the acridine ring are often destroyed. Thisreaction scheme is also labor intensive and performed under harshconditions. Accordingly, simple, economic processes for making acridineshave been sought.

N-arylation of amines was disclosed by Barton et al "Metallic CopperCatalysts of N-Arylation of Amines," Tetrahedron Letters, Vol. 27, No.31, pp. 3615-3618 (1986). However, amines are nucleophillic species, andare chemically reactive. By contrast, the amide (e.g. isatin) nitrogenis typically not considered nucleophillic. Presently, there is no goodmethod of converting an unsubstituted isatin to the N-aryl isatin.

SUMMARY OF THE INVENTION

The present invention is a simple, economical process for makingsubstituted acridine-9 carboxylic acids. Isatins are N-arylated withtriaryl bismuth reagents and copper or copper salts. The substituted, Narylated isatins are subsequently rearranged to produce substitutedacridines. This is a regiospecific (i.e. provides predominantly oneregioisomer) process, which allows direct synthesis of isomerically puresubstituted acridines in good yields. This process affords theproduction of acridines with different functional substitutions.

The process of the current invention involves the N-arylation of isatinsby (a) reacting a compound of formula I wherein A, B, C and D areselected independently in each instance from hydrogen, halogen, cyano,nitro, amino, carboxy, sulfone, and alkoxy, or B and C together can forma fused aromatic ring: ##STR1##

(b) with a compound of formula II: ##STR2## where X is selected from oneor more of hydrogen, halogen, nitro, cyano, alkyl and alkoxy. Z iseither a halogen or a substituent of formula III: ##STR3## with theproviso that where Z is a halogen, a salt of the formula ##STR4## isadded to the reaction mixture. Y is a group I or group II metal, and R*in each instance is selected from a group such that the conjugate acidof the group of formula III has a pka in water of less than 5.0. Thereaction above is performed in the presence of a copper catalyst toproduce an N-arylated isatin of formula IV: ##STR5## The N arylatedisatin of formula IV is treated with a strong base, and heated toproduce an acridine compound of formula V:

DETAILED DESCRIPTION

In this invention, as indicated above, an isatin of formula I is reactedwith a triaryl bismuth reagent of formula II in the presence of copperor a copper salt to produce an N-arylated isatin of formula IV which canbe converted to an acridine of formula V. The acridine can then beconverted to a chemiluminescent label as described in U.S. patentapplication Ser. No. 921,979 filed Oct. 22, 1986 which is incorporatedherein by reference.

As indicated above, the substituent R^(*) in formula III is selectedfrom a group such that the conjugate acid of the group of formula IIIhave a pKa in water of less than 5.0. By "conjugate acid of the group offormula III" is meant an acid of the formula: ##STR7## Preferredsubstituents for R^(*) include hydrogen, cyano, alkyl, halo substitutedalkyl or cyano substituted alkyl. The most preferred substituents forR^(*) include trifluoromethyl or methyl.

Further details of the foregoing scheme are described in examples thatfollow. In these examples, two general approaches are described. First,the bismuth arylating reagent can be presynthesized as described inExample 1. Alternatively, the bismuth arylating reagent can be generatedin situ (i.e. during the arylation of the isatin) as illustrated in thefollowing reaction scheme and in Example 3(b). ##STR8## where Y is agroup I or group II metal), Z is a halogen, is an aryl, and X is asdefined above.

The following examples illustrate the preparation of N-arylated isatinsand acridines. The conversion of acridines to chemiluminescent compoundsis described in the foregoing U.S. patent application.

Reference to symbols such as X,A, B, C and the like in the followingexamples correspond to the meanings those symbols have been given above.

EXAMPLE 1 Synthesis of Triphenyl Bismuth Diacetate

Silver acetate (5.12 grams) and water (1 1) were placed in a 3 1 roundbottom flask, kept under a nitrogen atmosphere, and the flask wascovered with foil. To this suspension were added triphenyl bismuthdichloride (Ph₃ BiCl₂ Alfa Products, Danvers, MA; 7.06 grams) andbenzene (800 ml). The mixture was stirred mechanically in the dark fortwo days.

The mixture was then suction filtered, and the residue was rinsed withbenzene (50 ml). The white, insoluble residue (which discolors to aviolet tint) was discarded. The two phase filtrate was then placed in aseparatory funnel. The two layers were then separated, and the aqueouslayer discarded. The benzene layer was then evaporated to a volume of200 ml. Petroleum ether (700 ml) was added. A white precipitate formsand was collected by suction filtration. The filtrate was driedovernight under a vacuum, yielding 4.91 g of triphenyl bismuth diacetate(X═H). NMR 1.80 (6H,s); 7.67 (9H,m); 8.19 (6H,m); Ms m/z @499(M--OCOCH₃).

EXAMPLE 2 Synthesis of N-phenyl Isatin

Isatin (25 mg from Aldrich, Milwaukee, Wisconsin) was placed in a 25 mlround bottom flask under a nitrogen atmosphere. Triphenyl bismuthdiacetate (300 mq) from Example 1 and freshly distilled methylenechloride (from P₂ O₅ ; 10 ml) was then added, maintaining the nitrogenatmosphere. Copper powder (3 mg) was then added. The reaction mixturewas then stirred at reflux for four hours. An additional portion oftriphenyl bismuth diacetate (95 mg) was added, and the mixture wasrefluxed for twelve hours more. The desired product, N-phenyl isatin(42.1 mg) was obtained and purified on a 2 mm silica prep plate(ANALTECH UNIPLATE Silica Gel GF. 1:1 hexane/ethyl acetate).

Melting point: 138°-139.5° C.,

NMR: δ6.90 (lH,d), 7.17 (lH,t), 7.50 (6H,m), 7.69 (lH,d) ppm ,

MS: (M+)@223

EXAMPLE 3 Synthesis of N phenyl 5 nitroisatin

a) 5-Nitroisatin (53 mg; Aldrich N 1780 7), triphenyl bismuth diacetate(304 mg), and freshly distilled methylene chloride (about 10 ml) wereplaced in a 25 ml flask under a nitrogen atmosphere. To this dull yellowsuspension, copper powder (5 mg) was added. For seven hours, the mixturewas then heated to reflux by placing it in an oil bath while stirringthe mixture. Additional triphenyl bismuth diacetate (95 mg) was addedand allowed to stir at reflux overnight. The mixture was evaporated todryness and purified on a 2mm silica plate as in example 2. An orangeresidue (56.3 mg) was obtained.

(A═H, B═H, C═NO2, D═H, X═H),

NMR: δ7.15 (lH,d), 7.52 (5H,m), 8.46 (lH,d), 8.55 (1H,s) ppm

MS: (M+)@268

b) Alternatively, N-phenyl 5 nitroisatin was prepared by the in-situbismuth arylating reagent generation scheme outlined above.5-nitroisatin (100.3 mg), triphenyl bismuth dichloride (400 mg), copperpowder (10 mg), and methylene chloride (40 ml) were placed in a 50 mlflask. The mixture was heated to reflux under a nitrogen atmospherewhile stirring. After three hours, no reaction was observed althoughbismuth reagent decomposition was noted whereupon additional triphenylbismuth dichloride (220 mg) was added. The mixture was stirred andrefluxed overnight after which arylation was still not observed.

Then, sodium acetate (300 mg) and triphenyl bismuth dichloride (200 mg)were added together to the mixture. The mixture was refluxed overnight,and more sodium acetate (150 mg) and triphenyl bismuth dichloride (200mg) were added. The reaction mixture was cooled to room temperature andfiltered. The filtrate was evaporated to dryness. The orange residueproduced was purified on 3×2 mm silica prep plates (as in example 2).Analysis of the residue (48 mg) confirmed that the title compound wasprepared.

(A═H, B═H, C═NO2, D═H, X═H).

NMR: δ7.15 (lH,d), 7.52 (5H,m), 8.46 (lH,d), 8.55 (1H,s) ppm

MS: (M+)@268

EXAMPLE 4 Synthesis of N phenyl benz[f]isatin

Linear benz[f]isatin (Eteine, A.; Staehelin, A.; Bull. Chim. Soc. Fr.,1954, 243-748) (50 mg), triphenyl bismuth diacetate (354 mg), andmethylene chloride (about 15 ml) were placed into a 25 ml flask under anitrogen atmosphere. To this bright orange mixture was added copperpowder (4.5 mg). The mixture was then heated to reflux while stirringfor 12 hours.

Additional triphenyl bismuth diacetate (50 mg) and methylene chloride (3ml) were added, and the mixture was refluxed for 48 hours. The mixturewas dried, and purified on a 2 mm silica plate (4:6 ethylacetate/hexanes). A red solid (20.5 mg) was obtained.

(A═H, B&C═fused phenyl; D═H, X═H)

NMR: δ7.05 (1H,s); 7.52 (8H,m); 7.94 (lH,d); 8.27 (1H,s) ppm.

MS: (m +H)@274:

EXAMPLE 5 Synthesis of N phenyl 5 bromoisatin

5 Bromoisatin (55 mg; Aldrich No. 12, 407-9), triphenyl bismuthdiacetate (340 mq) and methylene chloride (about 15 ml) were placed in a25 ml flask under a nitrogen atmosphere. To this yellow solution wasadded copper powder (4.5 mg). The mixture was then heated to reflux inan oil bath while stirring for 24 hours. Additional triphenyl bismuthdiacetate (90 mg), and methylene chloride (3 ml) were added, and themixture was refluxed for 12 hours. Finally, additional (triphenylbismuth diacetate; 59 mg) and methylene chloride (3 ml) were added, andthe mixture refluxed for two more days.

The mixture was suction filtered through Celite®, and rinsed withethylacetate. The reddish yellow residue was dried, and purified on a 2mm silica plate (4:6 ethylacetate/hexanes). The purified residue weighed26.8 mg.

(A═H, B═D═X═H, C═Br)

NMR: δ6.72 (lH,d); 7.52 (6H,m); 7.80 (1H,s)

MS: (M+)@301, 303

EXAMPLE 6 Synthesis of N phenyl 5-methylisatin

5-Methylisatin (53 mg; Aldrich No. 22, 242-9), triphenyl bismuthdiacetate (278 mg), copper powder 5 mg), and methylene chloride (about15 ml) were placed in a 25 ml flask under a nitrogen atmosphere. Theorange solution was then heated to reflux in an oil bath for fourteenhours. Then, additional triphenyl bismuth diacetate (154 mq) was added,and the mixture was refluxed for eight hours. Additional triphenylbismuth diacetate (158 mg) was added, and the mixture was refluxed forabout twelve hours. The heat was then removed, and the mixture wasstirred for two days.

The mixture was suction filtered through Celite®and evaporated todryness. The mixture was purified on 32 mm silica plates (4:6ethylacetate/hexanes) and 57.3 mg of the title compound was obtained.

(A═H, B═D═X═H, C═CH3)

NMR: δ2.30 (3H,s); 7 52 (lH,d); 7.19 (8H,m)

MS: (m+H)@238

EXAMPLE 7 Synthesis of N phenyl 5 cyanoisatin

5-cyanoisatin [prepared by the method of Gassman, et. al., J. Org.Chem., 42, 1344 (1977)](50 mg, 0.29 mmoles), triphenyl bismuth diacetate(300 mq) and copper powder (3 mg) were added to 10 mL of methylenechloride (freshly distilled). The reaction mixture was heated to refluxunder nitrogen for a total of 16 hours during which additional triphenylbismuth diacetate (95 mg) was added at four hour intervals. The productwas isolated after evaporating the reaction mixture to dryness thenpurifying by preparative TLC as in example 2.

(A═H, B═H, C═CN, D═H, X═H)

EXAMPLE 8 Synthesis of N phenyl 5 carboxy methyl isatin

5-carboxy methyl isatin [Bauer, et al., Brit J. Pharmacol, 15, 101(1960)](50 mg, 0.24 mmoles), triphenyl bismuth diacetate (300 mg) andcopper powder (3 mq) were added to methylene chloride (10 mL). Thereaction mixture was refluxed under nitrogen for 16 hours during whichtime additional triphenyl bismuth diacetate (95 mg) was added at fourhour intervals.

N-phenyl 5 carboxy methyl isatin was isolated after evaporation of thereaction mixture and purification by preparative TLC as in example 2.

(A═H, C═CH₂ CO₂ H, B═H, X═H)

EXAMPLE 9 Synthesis of N phenyl 5 amino isatin

5 amino isatin [Ger. Offen. 2,144,877]was treated with di-t butyldicarbonate [Aldrich, #20,524 9]in tetrahydrofuran water (1:1) in thepresence of an equivalent amount of triethyl amine. After stirringovernight at room temperature, the reaction mixture was diluted withethyl acetate and washed with dilute hydrochloric acid, brine and driedover MgSO₄. 5 (N-^(t) Boc-amino)isatin was isolated on evaporation.

This material (50 mg, 0.19 mmoles), triphenyl bismuth diacetate (300 mg)and copper powder (3 mg) was heated to reflux in 10 mL of methylenechloride under nitrogen for 16 hours, with the addition of moretriphenyl bismuth diacetate at four hour intervals.

The N-phenyl-5-(N-^(t) BOC-amino)isatin was isolated as in example 2,then treated with trifluoroacetic acid in methylene chloride at 0° C for30 minutes under nitrogen. N-phenyl-5-amino isatin was isolated onevaporation of the reaction mixture.

(A═H, C═NH₂, B═H, X═H)

EXAMPLE 10 Synthesis of N phenyl-5-methoxy isatin

5 methoxy isatin [Bachman, et al., J. Amer. Chem. Soc., 1599 (1946)].(50 mg, 0.28 mmoles), triphenyl-bismuth diacetate (300 mg) and copperpowder (3 mg) were heated to reflux in methylene chloride (10 mL) undernitrogen for 12 hours with the addition of more triphenyl bismuthdiacetate (95 mg) at four hour intervals.

N-phenyl 5-methoxy isatin was isolated as in example 2.

(A═H, C═OCH₃, B═H, X═H)

EXAMPLE 11 Synthesis of N phenyl-isatin 5 sulfonic acid

Isatin 5-sulfonic acid (Aldrich, #14,933-0) (50 mg, 0.2 mmoles),triphenyl bismuth diacetate (300 mg) and copper powder (3 mg) wereheated to reflux in methylene chloride (10 mL) under nitrogen for 24hours with addition of additional amounts of triphenyl bismuth diacetate(4×95 mg) over that time.

N phenyl isatin 5 sulfonic acid was isolated after evaporation of thereaction mixture, and purified on C-18 reversed phase preparative TLCplates [2, lmm Whatman PLKC18F].

(A═H, B═H, C═SO₃ H, X═H)

EXAMPLE 12 Synthesis of N-phenyl 7 methyl isatin

7-methyl isatin [Gassman et al., J. Orq. Chem., 42, 1344 (1977)]wastreated with triphenyl bismuth diacetate and copper powder as in example6 to yield N phenyl 7 methyl isatin.

(A═CH₃, B═H, C═H, X═H)

EXAMPLE 13 Synthesis of N phenyl 6-methyl isatin

6-methyl isatin [Grimshaw, et al., Synthesis, 496 (1974)]was treatedwith triphenyl bismuth dracetate and copper powder as in example 6 toyield N phenyl-6-methyl isatin.

(A═H, B═CH₃, C═H, X═H)

EXAMPLE 14 Synthesis of N phenyl 5-(2 aminoethyl)isatin

4-nitrophenethyl amine hydrochloride [Aldrich #18,480-2]was treated withdi-t-butyl dicarbonate in tetrahydrofuran with excess triethyl amine toform N- ^(t) Boc (4 nitrophenethyl)amine. Reduction with 5% pd/c inmethanol (50 psi H₂) yielded N-^(t) Boc-(4 aminophenethyl)amine.Treatment with oxalyl chloride and cyclization gives the isatin[Baumgarten, et. al, J. Org. Chem., 1961, 26, 1536]. This material wastreated with triphenyl bismuth diacetate as in example 8, to yield Nphenyl 5-(N-t-Boc 2 amino ethyl) isatin. The t-Boc protecting group wasremoved as in example 8 to give N-phenyl 5 (2-aminoethyl)-isatin.

(A═H, B═H, C═CH₂ CH₂ NH₂, X═H)

EXAMPLE 15 Synthesis of N (4-methoxy phenyl)isatin

Tri-(4 methoxy phenyl)bismuth dichloride [Barton, et al., Tetrahedron,42, 3111 (1986)]was converted to this diacetate following the procedurein example 1. Using this material, isatin was converted to N-(4-methoxyphenyl)isatin as in example 2.

(A═H, B═H, C═H, X═OCH₃)

EXAMPLE 16 Synthesis of N-(4 nitrophenyl)isatin

Tri (4-nitrophenyl)bismuth dichloride [Barton, et al., Tetrahedron, 42,3111 (1986)]was converted to this diacetate as in example 1. Thearylation of isatin as in example 2 led to N-(4-nitrophenyl)isatin.

(A═H, B═H, C═H, X═4 NO₂)

EXAMPLE 17 Synthesis of N-(3-nitrophenyl)isatin

Tri-(3-nitrophenyl)bismuth dichloride [Ptitsyna, et al., Chem. Abst.,57, 15147 (1962)]was converted to the diacetate as in example 1. Thearylation of isatin as in example 2 led to N-(3 nitrophenyl)isatin.

(A═B═C═H, X═3 NO₂)

EXAMPLE 18 Synthesis of N-(o-tolyl)isatin

o-Tolyl magnesium bromide (Aldrich 29, 898 0) was converted to tri-(otolyl)bismuth dichloride on reaction with bismuth trichloride (Aldrich#22, 483 9) following the procedure outlined in Barton, et al.,Tetrahedron, 42, 3111 (1986). The diacetate was formed as in example 1.The arylations of isatin as in example 2 led to N-(o tolyl)isatin.

(A═B═C∇H, X═2 CH₃)

EXAMPLE 19 Synthesis of Benz[b]acridine 12 carboxylic acid

The title compound can be prepared by placing N phenyl-benz [f]isatin(16 mg) from Example 4 and 10% KOH solution (10 ml) into a 35 ml flask.The bright orange solution is heated overnight on a steam bath in thedark.

The bright orange solution is removed from the steam bath and suctionfiltered to remove an orange brown precipitate of benz[b]acridin 12-one.The filtrate is acidified to pH 0 to 1 with concentrated hydrochloricacid. A purple precipitate is formed and collected by suctionfiltration.

(A═H, B&C=fused phenyl; D═X═H)

NMR: (CD₃ OD/NaOD) 7.2-7.5 (4Hm); 7.8 (2H (2H,m); 8.83 (lH,s); 8.93(lH,s),

MS: (m+64)@337 corresponding to the hydrate+2 Na

EXAMPLE 20 Synthesis of 2 bromo acridine 9 carboxylic acid

The title compound can be prepared by placing N phenyl-5 bromoisatin (20mq) from Example 5 and 10% KOH solution (10 ml) in a 25 ml flask. Thebright yellow mixture is heated in a steam bath overnight.

The solution is suction filtered, and the filtrate is acidified withconcentrated hydrochloric acid to pH 0 to 1. A bright yellow precipitateforms, and is collected by suction filtration.

(A═B═H, C═Br, D═H, X═H)

NMR: (CD₃ OD/NaOD) 7.66 (lH,m); 7.9 (2H,m); 8.22 (3H,m); 8.46 (lH,s)

MS: (m+)@301,303

EXAMPLE 21 Synthesis of 2 methyl acridine 9 carboxylate

The title compound can be prepared by placing N-phenyl-5 methyl isatin(40 mg) from Example 6 and 10% KOH solution (10 ml) in a 25 ml flask.The orange mixture is then heated overnight on a steam bath. The clearyellow solution is then filtered, and the filtrate is acidified to pH 0to 1 with concentrated hydrochloric acid. A bright yellow precipitateforms and is collected by suction filtration.

(A═B═H, C═CH₃, D═X═H)

NMR: (CD₃ OD/NaOD) δ2.54 (3H,s); 7.66 (3H,m); 8.08 (4H,m)

MS: (m+)@237

EXAMPLE 22 Synthesis of 2-nitro-acridine-9-carboxylic acid

The title compound can be prepared by placing N-phenyl 5 nitroisatin (40mg) from Example 3 and 10% KOH solution (10 ml) into a 25 ml flask. Thedark amber mixture is then heated overnight on a steam bath. The darkbrown solution is then suction filtered to collect a black insolublesolid. The filtrate is acidified to pH 0 to 1 with concentratedhydrochloric acid. The dark brown filtrate is then filtered, and thegolden brown filtrate is neutralized to pH 7-8 and evaporated todryness.

The collected precipitate from acidification is placed under a highvacuum, and evaporated to dryness.

(A═B═D═X═H; C═NO₂)

EXAMPLE 23 Synthesis of 2 cyano acridine 9 carboxylic acid

The title compound can be prepared from N-phenyl 5 cyano isatin ofexample 7 and 10% KOH by heating for 12 h on a steam bath. The solutionis filtered, then acidified to pH 1 with concentrated sulfuric acid andthe product collected by filtration.

(A═B═H, C═CN, X═H)

EXAMPLE 24 Synthesis of 2 carboxymethyl acridine 9 carboxylic acid

The title compound can be prepared from N phenyl-5 carboxy methyl isatinof example 8 and 10% KOH by heating for 12 h on a steambath. Thesolution is filtered, then acidified to pH 1 with conc. sulfuric acid,and the product is collected by filtration.

(A═B═H, C═CH₂ COOH, X═H)

EXAMPLE 25 Synthesis of 2 amino-acridine 9 carboxylic acid

The title compound can be prepared from N-phenyl-5 amino isatin ofexample 9 and 10% KOH by heating for 12 hours on a steam bath. Thesolution is filtered, then acidified with conc. sulfuric acid. Theproduct is collected by filtration.

(A═B═H, C═NH₂, X═H),

EXAMPLE 26 Synthesis of 2-methoxy acridine 9 carboxyl acid

The title compound can be prepared from N-phenyl-5-methoxy isatin ofexample 10 and 10% KOH by heating 2 hours on a steam bath. The solutionis filtered, then acidified to pH 1 with conc. sulfuric acid. Theproduct is collected by filtration.

(A═B═H, C═OOH₃, X═H)

EXAMPLE 27 Synthesis of 2-sulfo acridine-9-carboxylic acid

The title compound can be prepared from N-phenyl isatin 5 sulfonic acidof example 11 and 10% KOH by heating for hours on a steam bath. Thesolution is filtered, then acidified to pH 1 and product is collected byfiltration.

(A═B═H, C═SO₃ H, X═H)

EXAMPLE 28 Synthesis of 4 methyl acridine 9 carboxylic acid

The title compound can be prepared from N phenyl 7-methyl isatin ofexample 12 and 10% KOH by heating for hours on a steam bath. Thesolution is filtered, then acidified to pH 1 with concentrated sulfuricacid, and then product collected by filtration. (A═CH₃, B═C═X═H)

EXAMPLE 29 Synthesis of 3 methyl acridine 9-carboxylic acid

The title compound can be prepared from N-phenyl-6 methyl isatin ofexample 13 and 10% KOH by heating on a steam bath for 12 hours. Thesolution is filtered, then acidified to pH 1 with concentrated sulfuricacid, and the product is collected by filtration.

(A═C═D═H, B═CH₃, X═H),

EXAMPLE 30 Synthesis of 2-aminoethyl-acridine-9 carboxylic acid

The title compound can be prepared from N-phenyl-5-(2-amino-ethyl)isatinof example 14 and 10% KOH by heating for 12 hours on a steam bath. Thesolution is filtered, then acidified with concentrated sulfuric acid topH 1, and the product is collected by filtration.

(A═B═D═X═H, C═CH₂ CH₂ NH₂),

EXAMPLE 31 Synthesis of 2-methoxy acridine 9 carboxylic acid

The title compound can be prepared from N (4-methoxy phenyl) isatin ofexample 15 and 10% KOH by heating for 12 hours on a steam bath. Theproduct is isolated as in example 25.

EXAMPLE 32 Synthesis of 1(3)nitro acridine 9-carboxylic acid

The title compound can be prepared from N-(3 nitrophenyl) isatin ofexample 17 and 10% KOH by heating for 12 hours on a steam bath. Thesolution is filtered, then acidified to pH 1 with conc. sulfuric acid,and the mixture of products isolated by filtration.

(A═B═C═H, X═1 NO₂ or 3-NO₂)

EXAMPLE 33 Synthesis of 4 methyl-acridine-9-carboxylate

The title compound can be prepared from N-(o-tolyl)isatin of example 18and 10% KOH by heating for 12 hours on a steam bath. The product isisolated as in example 26.

(A═B═C═H, X═4═CH₃)

I claim:
 1. A process for N-arylation of isatins, comprising:(a) reacting a compound of formula I wherein A,B,C, and D are selected independently in each instance from hydrogen, halogen, cyano, nitro, amino, carboxy, sulfone, alkyl, and alkoxy, or B and C together can form a fused aromatic ring; ##STR9## (b) with a compound of formula II: ##STR10## wherein Z is a halogen or a substituent of formula ##STR11## with the proviso that where Z is a halogen, a salt of the formula ##STR12## is added to the reaction of compounds I and II where Y is a group I or group II metal, and R^(*) in each instance is selected from a group such that the conjugate acid ##STR13## of the group of formula II has a pKa in water of less than 5.0 and is other than trifluoroacetic acid; (c) in the presence of a copper catalyst; whereby an N-arylated isatin of formula III is produced; ##STR14##
 2. The process of claim 1 wherein R^(*) is selected from hydrogen, alkyl, halo-substituted alkyl, or cyano-substituted alkyl.
 3. The process of claim 2 wherein R^(*) is methyl.
 4. A process of claim 1 wherein the reaction mixture is heated to reflux temperature during the reaction.
 5. A process of producing an intermediate of formula IV, comprising:(a) reacting a compound of formula I; ##STR15## (b) with a compound of formula II; ##STR16## (c) in the presence of a copper catalyst to produce an N-arylated isatin of formula III; ##STR17## (d) and treating the N-arylated isatin of formula III with a strong base and heat to produce a compound of formula IV: ##STR18## wherein A,B,C, and D are selected independently in each instance from hydrogen, halogen, cyano, nitro, amino, carboxy, sulfone, alkyl, and alkoxy, or B and C together can form a fused aromatic ring; wherein X is selected from hydrogen, halogen, nitro, cyano, alkyl, and alkoxy; and R^(*) is selected from a group such that the conjugate acid ##STR19## of the group of formula II has a pKa in water of less than 5.0 and is other than trifluoroacetic acid.
 6. The process of claim 5 wherein R^(*) is selected from hydrogen, alkyl, halo-substituted alkyl, or cyano-substituted alkyl.
 7. The process of claim 6 wherein R^(*) is methyl.
 8. The process of claim 5 wherein the compound of formula II is generated in situ by reacting a compound of the formula ##STR20## with a compound of the formula ##STR21## wherein X is selected from hydrogen, halogen, nitro, cyano, alkyl, and alkoxy; R^(*) is selected from a group such that the conjugate acid ##STR22## of the group of formula II has a pKa in water of less than 5.0 and is other than trifluoroacetic acid; and wherein Z is a halogen and Y is an alkali metal. 